⁴⁴Sc: An Attractive Isotope for Peptide-Based PET Imaging

The overexpression of integrin α_vβ₃ has been linked to tumor aggressiveness and metastasis in several cancer types. Because of its high affinity, peptides containing the arginine–glycine–aspartic acid (RGD) motif have been proven valuable vectors for noninvasive imaging of integrin α_vβ₃ expression and for targeted radionuclide therapy. In this study, we aim to develop a ⁴⁴Sc-labeled RGD-based peptide for <i>in vivo</i> positron emission tomography (PET) imaging of integrin α_vβ₃ expression in a preclinical cancer model. High quality ⁴⁴Sc (<i>t</i>_1/2, 3.97 h; β⁺ branching ratio, 94.3%) was produced inexpensively in a cyclotron, via proton irradiation of natural Ca metal targets, and separated by extraction chromatography. A dimeric cyclic-RGD peptide, (cRGD)₂, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with ⁴⁴Sc in high yield (>90%) and specific activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG tumor xenografts showed elevated ⁴⁴Sc-DOTA-(cRGD)₂ uptake in the tumor tissue of 3.93 ± 1.19, 3.07 ± 1.17, and 3.00 ± 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively (<i>n</i> = 3), which were validated by <i>ex vivo</i> biodistribution experiments. The integrin α_vβ₃ specificity of the tracer was corroborated, both <i>in vitro</i> and <i>in vivo</i>, by competitive cell binding and receptor blocking assays. These results parallel previously reported studies showing similar tumor targeting and pharmacokinetic profiles for dimeric cRGD peptides labeled with ⁶⁴Cu or ⁶⁸Ga. Our findings, together with the advantageous radionuclidic properties of ⁴⁴Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of ⁴⁷Sc in theranostic applications